Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

  • Bioorg Med Chem. 2013 Nov 1;21(21):6582-91. doi: 10.1016/j.bmc.2013.08.025.
David A Sandham  1 ,  Nicola Arnold ,  Heinrich Aschauer ,  Kamlesh Bala ,  Lucy Barker ,  Lyndon Brown ,  Zarin Brown ,  David Budd ,  Brian Cox ,  Cerys Docx ,  Gerald Dubois ,  Nicholas Duggan ,  Karen England ,  Brian Everatt ,  Marcus Furegati ,  Edward Hall ,  Frank Kalthoff ,  Anna King ,  Catherine J Leblanc ,  Jodie Manini ,  Josef Meingassner ,  Rachael Profit ,  Alfred Schmidt ,  Jennifer Simmons ,  Bindi Sohal ,  Rowan Stringer ,  Matthew Thomas ,  Katharine L Turner ,  Christoph Walker ,  Simon J Watson ,  John Westwick ,  Jennifer Willis ,  Gareth Williams ,  Caroline Wilson
Affiliations
  • 1. Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: [email protected].
PMID: 24021582 DOI: 10.1016/j.bmc.2013.08.025
Abstract

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Keywords
13,14-dihydro-15-keto-PGD(2); 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine; Allergy; BAL; BEMP; CC chemokine receptor 3; CCR-3; CRTh2; CRTh2 receptor antagonist; DK-PGD(2); ELSD; FITC; GLP; PGD(2); SC; bronchoalveolar lavage; chemoattractant receptor homologous expressed on Th2 cells; evaporative light scattering detection; fluorescein isothiocyanate; good laboratory practice; prostaglandin D(2); shape change.
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